MECHANISMS OF ARTERIAL GRAFT HEALING

动脉移植物愈合机制

• 批准号: 7958848
• 负责人: ALEXANDER W CLOWES
• 金额: $ 15.76万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958848
• 关键词: Accounting; Alteplase; Arteries; Atrophic; Blood Vessels; Blood flow; Cell Death; Cell physiology; Cessation of life; Computer Retrieval of Information on Scientific Projects Database; DNA Microarray Chip; Down-Regulation; Extracellular Matrix; Funding; Genes; Grant; Human; Hyaluronidase; Hyperplasia; In Vitro; Institution; Intervention; Investigation; Link; Modeling; Papio; Polytetrafluoroethylene; Primates; Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Small Interfering RNA; Smooth Muscle Myocytes; Source; Stents; Testing; United States National Institutes of Health; Veins; cell growth; graft healing; iliac artery; in vivo; prevent; research study; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Approximately 30% of vascular interventions (for example, grafts and stents) develop lumenal narrowing and fail largely as a result of smooth muscle cell (SMC) growth, neointimal hyperplasia, and wall thickening. While most research has been directed at preventing neointimal hyperplasia, an alternative might be to stimulate neointimal atrophy after lumenal narrowing has developed. We have demonstrated that high blood flow induces neointimal atrophy in baboon PTFE grafts, but not in the normal iliac artery. In addition, a tight PTFE wrap around the baboon iliac artery causes significant atrophy of the wall.We have conducted a DNA microarray experiment to identify genes that are regulated during atrophy in both models (i.e. graft neointima and wrapped artery) and have found 15 genes (9 increased and 6 decreased). Of these, 8 of 9 upregulated genes and 3 of 6 down-regulated genes were verified by quantitative RT-PCR. Upregulated genes included the extracellular matrix degrading factors ADAMTS4, tissue plasminogen activator, and hyaluronidase 2. We have found that stimulation of cell death using FasL increases the expression of 5 of the verified upregulated genes and decreases expression of 2 of the verified down-regulated genes in cultured smooth muscle cells, thus linking these genes to the cell death observed during atrophy in vivo. Further experiments are underway to determine if down-regulation of ADAMTS4, tissue plasminogen activator, or hyaluronidase 2 using siRNA will alter the death response to FasL treatment in vitro. We have also begun to explore the implications of the baboon results in an investigation of human vein graft SMCs to test the hypothesis that the variability in significant graft narrowing (25% of grafts) can be accounted for by a hyperproliferative response of the endogenous cells and that the process might be reversed by inducing cell death and intimal atrophy.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 由于平滑肌细胞（SMC）生长，新内膜增生和壁增厚，大约30％的血管干预措施（例如移植物和支架）在很大程度上发生了肿瘤变窄和失败。虽然大多数研究都是针对预防新内膜增生的，但替代方法可能是刺激腔内变窄后刺激新内膜萎缩。 我们已经证明，高血流量会诱导狒狒PTFE移植物中的新内膜萎缩，但没有在正常的动脉中。此外，在狒狒小动脉周围进行紧密的PTFE包裹会引起壁的显着萎缩。我们进行了DNA微阵列实验，以识别两个模型中萎缩期间受调节的基因（即移植物和包裹的动脉），并发现了15个基因（9次增加和6个基因）。 其中，通过定量RT-PCR验证了9个上调的基因中的8个和6个下调基因中的3个。 Upregulated genes included the extracellular matrix degrading factors ADAMTS4, tissue plasminogen activator, and hyaluronidase 2. We have found that stimulation of cell death using FasL increases the expression of 5 of the verified upregulated genes and decreases expression of 2 of the verified down-regulated genes in cultured smooth muscle cells, thus linking these genes to the cell death observed during atrophy in vivo.正在进行进一步的实验，以确定使用siRNA的ADAMTS4，组织纤溶酶原激活剂或透明质酸酶2的下调是否会改变体外对FASL处理的死亡反应。我们还开始探索狒狒的含义导致对人静脉移植SMC的研究，以检验以下假设：显着狭窄（25％的移植物）的可变性可以通过内源性细胞的过度增强反应来解释，并且该过程可能通过诱导细胞死亡死亡和直肠性疾病而逆转。